Blumenthal R D, Sharkey R M, Forman D, Wong G, Goldenberg D M
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Newark, New Jersey 07103.
Cancer. 1994 Feb 1;73(3 Suppl):1083-92. doi: 10.1002/1097-0142(19940201)73:3+<1083::aid-cncr2820731348>3.0.co;2-3.
The authors recently reported that a 12-day schedule (beginning 3 days before radioantibody treatment) of twice-daily dosing of rH-IL-1 (1 x 10(3) U/dose) and rM-GM-CSF (0.5 micrograms/dose) can reduce the magnitude and duration of radioantibody-induced myelosuppression, thereby permitting a 25-30% increase in the dose of radioantibody that can be administered without the dose proving lethal. In an effort to further reduce toxicity and escalate the tolerated dose, the authors altered the method of administration of cytokines from daily bolus dosing to continuous infusion by implantable osmotic pumps.
A control group of mice was compared to five groups of mice that either did or did not receive a 340 microCi dose of radioantibody, and received no cytokines, cytokines by bolus dosing, or cytokines by continuous infusion. For 4 weeks, peripheral white blood cell and thrombocyte counts and thymus and spleen weights were taken, marrow cell number was monitored, and marrow colony-forming unit activity was evaluated weekly in the untreated control mice and the treated mice.
These studies demonstrated that after a dose of radioantibody, continuous dosing of cytokines resulted in higher white blood cell (WBC) and platelet values than if bolus delivery was used (day 7, WBC: 110% vs. 59%; day 14, WBC: 85% vs. 62%; day 21, WBC: 98% vs. 42%; day 7, platelets: 122% vs. 51%; day 14, platelets: 159% vs. 72%; day 21, platelets: 239% vs. 171%). A comparison of bolus versus continuous dosing in the absence of radioantibody indicated that spleen weight increased by 40-60% after continuous infusion of cytokines and by 20-25% after bolus dosing. The 20-30% decrease in thymus weight was similar with both dosing regimens. Colony-forming units (CFUs) in marrow increased from 30-35 in untreated mice to 50-55 in mice given cytokines by bolus injection, and to 150-180 in mice given continuous infusion of cytokines. Spleen CFUs exhibited an insignificant increase after bolus dosing of cytokines but increased almost fourfold after continuous dosing. Peak stimulation of marrow and spleen CFUs occurred 28 days after initiation of cytokine administration (2 weeks after cytokines administration was stopped). The probability of survival for 6 weeks after further dose escalation to 360 microCi I-131-MN-14 immunoglobulin G was 16.4% +/- 8.6% after bolus dosing and 58.1% +/- 11.3% after continuous infusion of cytokines.
Although continuous infusion of cytokines proved to be a better method of reducing hematopoietic toxicity, further dose escalation of radioimmunotherapy using the "pump" method of cytokine delivery was not possible. Cytokine intervention by either mode of delivery permits a 25% dose intensification without the dose becoming lethal. Further escalation is not feasible, possibly because of other end organ toxicity.
作者最近报道，在放射性抗体治疗前3天开始的12天疗程中，每日两次给予重组人白细胞介素-1（rH-IL-1，1×10³U/剂量）和重组鼠粒细胞-巨噬细胞集落刺激因子（rM-GM-CSF，0.5μg/剂量），可减轻放射性抗体诱导的骨髓抑制的程度和持续时间，从而使可给予的放射性抗体剂量增加25%-30%，且该剂量不会致死。为了进一步降低毒性并提高耐受剂量，作者将细胞因子的给药方式从每日大剂量推注改为通过植入式渗透泵持续输注。
将一组对照小鼠与五组小鼠进行比较，这五组小鼠分别接受或未接受340微居里剂量的放射性抗体，且分别未接受细胞因子、接受大剂量推注细胞因子或接受持续输注细胞因子。在4周时间里，对未治疗的对照小鼠和治疗小鼠每周进行外周血白细胞和血小板计数、胸腺和脾脏称重，监测骨髓细胞数量，并评估骨髓集落形成单位活性。
这些研究表明，给予放射性抗体剂量后，持续输注细胞因子导致的白细胞（WBC）和血小板值高于大剂量推注给药（第7天，WBC：110%对59%；第14天，WBC：85%对62%；第21天，WBC：98%对42%；第7天，血小板：122%对51%；第14天，血小板：159%对72%；第21天，血小板：239%对171%）。在未给予放射性抗体的情况下，比较大剂量推注与持续输注给药发现，持续输注细胞因子后脾脏重量增加40%-60%，大剂量推注给药后增加20%-25%。两种给药方案导致的胸腺重量下降20%-30%相似。未治疗小鼠骨髓中的集落形成单位（CFU）从30-35个增加到接受大剂量推注细胞因子的小鼠的50-55个，以及接受持续输注细胞因子的小鼠的150-180个。大剂量推注细胞因子后脾脏CFU略有增加，但持续输注后增加近四倍。骨髓和脾脏CFU的峰值刺激在开始给予细胞因子后28天出现（停止给予细胞因子后2周）。将剂量进一步提高到360微居里I-131-MN-14免疫球蛋白G后，6周存活概率在大剂量推注给药后为16.4%±8.6%，在持续输注细胞因子后为58.1%±11.3%。
尽管持续输注细胞因子被证明是降低造血毒性的更好方法，但使用“泵”式细胞因子给药方法进一步提高放射免疫治疗剂量是不可能的。两种给药方式的细胞因子干预均可使剂量增加25%且不会致死。进一步提高剂量不可行，可能是由于其他终末器官毒性。
